HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 1, 237-243, January 4, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/1/237    most recent M704748200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Han, Z. Articles by Stacpoole, P. W. Search for Related Content PubMed PubMed Citation Articles by Han, Z. Articles by Stacpoole, P. W. Social Bookmarking                      What's this?

Pyruvate Dehydrogenase Complex Deficiency Caused by Ubiquitination and Proteasome-mediated Degradation of the E1β Subunit^*

Zongchao Han, Li Zhong, Arun Srivastava^¶, and Peter W. Stacpoole^¶||**1

From the Departments of Pediatrics, Division of Cellular and Molecular Therapy, Molecular Genetics and Microbiology, ^¶The General Clinical Research Center, ^||Medicine, Division of Endocrinology and Metabolism, and ^**Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610

Congenital deficiencies of the human pyruvate dehydrogenase (PDH) complex are considered to be due to loss of function mutations in one of the component enzymes. Here we describe a case of PDH deficiency associated with the PDH E1β subunit (PDHB) gene. The clinical phenotype of the patient was consistent with reported cases of PDH deficiency. Cultured skin fibroblasts demonstrated a 55% reduction in PDH activity and markedly decreased immunoreactivity for PDHB protein, compared with healthy controls. Surprisingly, nucleotide sequence analyses of cDNAs corresponding to the patient PDH E1 (PDHA1) and PDHB genes revealed no pathological mutations. Moreover, the relative expression level of PDHB mRNA and the rates of transcription and translation of the PDHB gene were normal. However, PDC activity could be restored in cells from this patient following treatment with MG132, a specific proteasome inhibitor, and normal levels of E1β could be detected in MG132-treated cells. Similar results were obtained following treatment with Tyr-phostin 23 (Tyr23), a specific inhibitor of epidermal growth factor receptor-protein-tyrosine kinase (EGFR-PTK), which also restored E1β protein levels to those in cells from healthy subjects or from patients with PDHA1 deficiency. The index patient's cells contained a high basal level of EGFR-PTK activity that correlated with the high level of ubiquitination of cellular proteins, although the total EGFR protein levels were similar to those in cells from El-deficient subjects and healthy subjects. These data indicate that PDH deficiency in our patient involves a post-translational modification in which EGFR-PTK-mediated tyrosine phosphorylation of the E1β protein leads to enhanced ubiquitination followed by proteasome-mediated degradation. They also provide a novel mechanism accounting for congenital deficiency of the PDH complex and perhaps other inborn errors of metabolism.

Received for publication, June 8, 2007 , and in revised form, September 10, 2007.

^* This work was supported in part by the Zachary Foundation and by National Institutes of Health Grants M01-000082 and P01 DK-058327. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine (Division of Endocrinology and Metabolism), 1600 SW Archer Rd., Gainesville, FL 32610. Tel.: 352-392-2321; Fax: 352-846-0990; E-mail: peter.stacpoole{at}medicine.ufl.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Chen, B. P. Mooney, M. Hajduch, T. Joshi, M. Zhou, D. Xu, and J. J. Thelen System Analysis of an Arabidopsis Mutant Altered in de Novo Fatty Acid Synthesis Reveals Diverse Changes in Seed Composition and Metabolism Plant Physiology, May 1, 2009; 150(1): 27 - 41. [Abstract] [Full Text] [PDF]